Cyclopentane-polyhydrophenanthrene derivatives



Patented Jan. 3, 1939 PATENT OFFICE OYCLOPENTANE-POLYHYDROPHENAN- THRENE DERIVATIVES Max Bockmiihl, Gustav Ehrhart, Heinrich Ruschig, and Walter Aum Main-Hochst, Germa Chemical Company,

iiller, Frankfort-on-theassignors to Winthrop Inc., New York, N. Y., a

corporation of New York No Drawing. Application February 12, 1938, Se-

3 I Claims.

The present invention relates to cyclopentanepolyhydrophenanthrene derivatives.

In U. S. application Serial No. 49,644, filed November 13, 1935, in the name of Max Bockmiihl, Gustav Ehrhart and Heinrich Ruschig, there is described a manufacture of ketones from the acids of the formula CH: RC:COOH

in which R stands for a tetracyclic hydro-aromatic ring system. According to this process in the course of which transformations occur in the ring 1 of the cyclopentane-polyhydrophenanthrene-radical and which is of importance for the preparation of sterol-like bodies there are obtained for instance sterol-like compounds with the side chains:

On further investigating this field it has ,been found that intermediate products or final bodies important in sterol chemistry are obtained by subjecting to a partial saponification compounds of the following general formula:

CH /CH3 CH: X k/ R AcO R wherein Ac stands for an acyl residue, at least one R stands for an acyloxy-residue whereas the second R may stand for hydrogen and X stands for a carbon atom with a bivalent residue, such as C=O, C=NH or with a secondarily bound NHz-group or OH-group, such as CHNH: or CHOH,

\ oxidizing the compounds of 3-hydroxy-cyclopeniial No. 190,324. In Germany February 20, 937

The process is performed for instance as follows: A derivative of 3:7:12-triacyl-hydroxycyclopentane-polyhydrophenanthrene with the side chain COCH3 in 17-position is carefully saponified, whereby only the ester group standing in 3-position is saponified. The product obtained, possessing a free hydroxyl group in 3-position, may now be oxidized to formthe keto-group and the ketone obtained may be halogenated, whereby the halogen enters into ortho-posltion to the 3-keto-group. By the separation of hydrogen halide a double bond is produced in the neighbouring position to the keto-group.

If in the 17-position of the cyclopentane ring there is present, instead of the keto-group, a ketimide-group or a secondary hydroxy-group or amino-group, there may advantageously be made from these compounds first substances with a side chain of the ketone character and then the ketones obtained may be subjected to the course of the manufacture described. With the same or a similar success the ketimide-compounds, hy-

droxy-compounds or amino-compounds named The process described above leads to compounds of the following general formula:

X CH:

wherein X stands for hydroxyl or an acyloxy residue and Y stands for hydrogen, hydroxyl or an acyloxy residue.

All these products are colorless crystals which readily dissolve in alcohol and chloroform but which sparingly dissolve in water.

The process which starts from the 3:12-diaoetoxy-pregnanone-20 of the following formula: CHLCO-O CHaCO and leads to the lz-acetoxyprogesterone of the following formula: I

CHaC0.0

CHI

5 and-by saponifying the last-named compound to the l2-hydroxyprogesterone of the following formula:

has proved to be especially important.

The compounds obtained according to the invention may be used as medicinal remedies or for the manufacture of such remedies.

The following example serves to illustrate the invention but it is not intended to limitit thereto:

' (a) 3:12-diawtosvpreananone-Z0 (b) 3-hvdroz1l-1 Z-acetozypregnanone 4 grams of the crude diacetyl compound are dissolved in cc. of methanol and 50 cc. of 2N-caustic soda solution are added thereto. The mixture is allowed to stand for 5% hour at room temperature and is then cautiously acidified by means of dilute sulfuric acid. A magma of fine 66 needles separates. It is dissolved in ether, the

ethereal solution is washed with sodium carbonate and water, dried by means of sodium sulfate and concentrated. Crystallization sets in if the residue is rubbed with ether. The impurities 70 contained in the residue are taken up by the ether and pure white crystals are obtained melting at 203 C. The yield amounts to 2.1 grams.

(c) IZ-acetoxvpreonandione-MO 1 2 grams of 3-hydroxy-l2-acetoxypregnan0nc- 20 are allowed to stand for 12 hours at room temperature in a mixture of 50 cc. of glacial acetic acid, 600 milligrams of chromic anhydride and a small quantity of water. The whole is rendered feebly alkaline by means of a dilute 5 lye extracted with ether and after having been washed with water the ethereal solution is dried with sodium sulfate. After distillation there are obtained 1.8 grams of 12-acetoxypregnandione in the form of a resin which crystallizes by rubbing 10 it with ether or petroleum ether. From dilute methanol the diketone is obtained in the form ofneedles melting at 132.5 C.

(a) IZ-acetoztflA-bromo-premndimw-SJD 1.8 grams of the crude pregnandione are dissolved ln 30 cc. of glacial acetic acid and after the addition of some drops ofhydrobromic acid 5 cc. of a molal solution of bromine in glacial acetic acid are added drop by drop. Each drop of I) the bromine solution is immediately consumed. The solution is poured into water and the separated flakes are filtered with suction, dissolved in ether and dried. By rubbing at the inside of the vessel with a glass rod crystals separate from as the ethereal solution which melt at C. while decomposing. The yield in crystallized acetoxybromopregnandione amounts to 1 gram.

(6) IZ-oceto-WWesierone o 1 gram of 12-acetoxy-4-bromo-pregnandione-8, 20 is boiled with 50 cc. of anhydrous pyridine for about 16 hours in a reflux apparatus. The light yellow solution is poured into dilute sulfuric acid and the crude raw acetoxyrprogesteroneisisolated N by extracting with ether. The product obtained after the distillation of the ether is free from bromine and crystallizes when being rubbed with ether. The ethereal solution is decanted. the crystals are dissolved in methanol, the solution is boiled with animal charcoal, filtered with suction and water is cautiously added. The acetoxyprogesterone crystallizes in the form of needles and after having been redissolved once more it melts at 181 0. The yield amounts to 500 milligrams of an analytically pure product.

(I) 1 Z-hudroxupfoqesterone 400 milligrams of 12-acetoxyprogesterone are saponified by boiling them for one hour with 5 50 cc. of 1.1 N-methylaleoholic caustic potash solution. After having been recrystallized from methanol the l2-hydroxyprogesterone melts at C. It crystallizes in the form of colorless x stands for a member of the group consisting of hydroxyl and an acyloxy residue and Y stands for a member of the group consisting of hydrogen, hydroxyl and an acyloxy resiis said compounds being colorless crystals readily 8. The compound of the following formulai soluble in alcohol and chloroform and sparingly soluble in water. 0H 7 2. The compound of the following formula: CH1 5 cmcoo 00.011. 5 cm I 0/ V 10 said compound forming colorless crystals readily soluble in alcohol and chloroform and sparingly 0/ I soluble in water, melting at 195 c. 15 MAX BOCK'M'UHL. 15

said compound forming colorless crystals readily V 1 -GUSTAV EHRHART. soluble in alcohol and chloroform and sparingly HEINRICH RUSCHIG.

soluble in water meltlng at 181 C. WALTER AUMULLER. 

